The long-term objective of this proposal is to understand how primary afferent neurons of the "pain" pathway detection noxious and transduce this information this information into action potentials, a process referred to as nociception. Identification of the molecular components involved in nociception should improve our understanding of how tissue injury produces both acute and persistent pain. In the past few years, a number of candidate molecules have been proposed to mediate responses of nociceptors to noxious thermal or chemical stimuli. These include the receptor for capsaicin and other vanilloid compounds (VR1), a vallinoid-insensitive, heat-sensitive VR1 homologue (VRL1), and members of the acid-sensing ion channel family (ASICs). In the proposed study, a combination of genetic, neuroanatomical, and electrophysiological methods will be used to assess the contribution of these molecules to nociception and pain in vivo. The specific aims of the proposal are to: (i) ascertain the relative contributions of VR1 and VRL1 to nociception by assessing the ability of mice bearing deletions in these genes to detect noxious physical and chemical stimulant; (ii) determine the involvement of VR1 and VRL1 in neurotrophin-mediated hyperalgesia by examining heat and chemical sensitivity of VR1 and VRL1 mutant mice in which nerve growth factor is transgenically over-produced in the skin; (iii) assess the relative contributions of VR1 and ASICs to acid sensitivity by generating VR1/ASIC double mutant mice and examining the sensitivity to noxious physical and chemical stimuli and the cellular and behavioral level. In addition to providing new information about the basic cellular mechanisms underlying nociception and pain, the proposed studies will highlight potential targets for the development of novel analgesic agents.